Adverse effects of Anticancer Chemotherapy in Childhood Cancer:

A Prospective Study in a Moroccan hospital

 

Casimir Adade Adade*1, Amine Cheikh2, Hafid Mefetah3, Amina Kili4, Laila Hessissen4, Mustapha Bouatia1,3

1Faculty of Medicine and Pharmacy of Rabat, Mohamed V University, 10170 Rabat, Morocco.

2Department of Pharmacy, Faculty of Pharmacy, Abulcasis University, 10000 Rabat, Morocco.

3Department of Pharmacy, Pediatric Hospital, 10170 Rabat, Morocco.

4Pediatric Hematology and Oncology Center, Mohamed V University, 10170 Rabat, Morocco.

*Corresponding Author E-mail: casimir.adade@gmail.com

 

ABSTRACT:

Objective: To determine the incidence and frequency of adverse drug reactions (ADRs) induced by cancer chemotherapy in pediatric inpatients. Patients and methods: This was a six-month prospective observational study in the pediatric hematology-oncology department of the children's hospital of Rabat. This study took into account ADRs manifested by in inpatient children and undergoing cancer chemotherapy. A modified version of the Moroccan Poison Control and Pharmacovigilance Centre's notification form was used to collect demographic, clinical, cancer treatment and ADR-related data. The causality, severity and preventability were assessed for each adverse event. Results: 106 patients out of 118 followed have developed a total of 266 ADRs. The most frequent ADRs were anemia (14.3%), infections (9.4%), leukopenia (8.6%) and fever (8.3%). Vincristine (16.3%), etoposide (14%) and cytarabine (13%) were the most frequently administered products. Cytarabine followed by etoposide were the drugs most involved in ADRs. The majority of ADRs (55.6%) were probable according to the WHO method of causality assessment. Conclusion: Cancer chemotherapy is associated with a high risk of developing ADRs, particularly hematological ADRs in children. Pediatric patients receiving cytarabine and daunorubicin combinations and regimens including anthracyclines should receive more attention. Risk management plans need to be implemented by health care teams in this area.

 

KEYWORDS: Pediatric, pharmacovigilance, adverse drug reactions, cancer, chemotherapy.

 

 


INTRODUCTION:

Pediatric cancer is one of the leading causes of death in children and its incidence is constantly increasing worldwide. Each year approximately 300,000 new cases are diagnosed in children aged 0-19 years. In low- and middle-income countries, the survival rate, which varies around 20%, is four times lower for children with cancer than in high-income countries1-4. In these countries, the toxicity of the therapies used contributes, in addition to diagnostic difficulties, inaccessibility of treatment and supportive care, to the high mortality rate5.

 

In Morocco, the survival rate is estimated at 30%, reflecting the considerable efforts made in recent years, in particular the equipping of four pediatric cancer centers with a total of 117 beds since 20126,7.

 

Chemotherapy plays an important role in the treatment of childhood cancer. Significant advances in treatment have been made continuously over the past few years in both chemotherapy, surgery and radiotherapy techniques8-11. However, cancer therapy, especially chemotherapy, still has significant toxicities compared to other classes of drugs. The detection and evaluation of adverse drug reactions (ADRs) related to drug treatments allows better management of the risks associated with their use12-15. As a result, pharmacovigilance research, particularly in children, has gained in importance in recent years16-18.

 

 

The most common ADRs related to anticancer drugs are well known in oncology: nausea, vomiting, constipation, fatigue, alopecia, drowsiness, myelosuppression, skin reactions, anorexia, mucositis and diarrhea19. Various studies have addressed the subject at the hospital level, but they have mainly concerned adults20-23.

 

The prevalence of ADRs can be very high in children for a variety of reasons. Pediatric patients have age-related specificities that may cause them to react differently after administration of a drug compared to adults24,25. In addition, dosing medications according to a child's weight and body surface area may be more complex26. These child-specific factors come on a field of oncology where the high number of drugs prescribed is also a risk factor for the development of an ADR27,28. The objective of our study was to determine the incidence and frequency of ADRs induced by cancer chemotherapy in pediatric inpatients.

 

Patients and Methods:

Study Design:

This was a prospective, observational study over a six-month period, from September 2018 to February 2019, at the Department of Pediatric Hematology-Oncology (DPHO) of the Children's Hospital of Rabat. The DPHO is intended to treat children affected by hematological diseases and solid tumors. This study had received authorization from the hospital administration.

 

The study involved all children (under 18 years of age) treated for cancer, who were hospitalized and undergoing inpatient chemotherapy. Patient demographic and clinical data and detailed information on chemotherapy (anticancer, dose, frequency, start and end date of treatment), associated treatments and the ADR that occurred were collected. This collection was done using a form designed from the ADR collection form of the Moroccan Anti-Poison and Pharmacovigilance Centre.

 

Causality study, assessment of severity and preventability:

Each ADR was subjected to a causality study according to the WHO method, looking for a causal link with the anticancer drugs administered. According to this method, ADRs were classified as certain, probable, possible, unlikely, unclassifiable, inaccessible29. ADRs were classified according to the CTCAE classification based on the classes of organs affected30. For each ADR, severity was assessed using the Hartwig-Siegel Severity Scale, and then rated as low, moderate and severe31. The preventability was obtained using the modified Shomock and Thoronton scale32.

 

 

RESULTS:

Socio-demographic and clinical characteristics of patients with adverse events:

During the period of study, 118 patients, including 68 (57.6%) boys, received chemotherapy. 106 patients developed at least one ADR. This represented an incidence of 89.8%. Sixty-two (58.5%) patients were male. The median (interquartile range) age was 7.6 years [3.5 - 10.8]. The majority of patients were in the 6-12 year age group. The most common types of cancer were leukemia (39.7%), neuroblastoma (14.2%) and Ewing sarcoma (12.3%) [Table 1].

 

Table 1: Socio-demographic and clinical characteristics of patients with ADR

Variables

n (%)

Sex

 

Male

62 (58.5)

Female

44 (41.5)

Age

 

£ 3

16 (15.1)

From 3 to 6

26 (24.5)

From 6 to 12

44 (41.5)

From 12 to 18

20 (18.9)

Type of cancer

Acute lymphoblastic leukemia

22 (20.8)

Acute myeloid leukemia

20 (18.9)

Neuroblastoma

15 (14.2)

Ewing sarcoma

13 (12.3)

Others

36 (34)

Type of chemotherapy

 

Monotherapy

41 (23.7)

Bitherapy

61 (35.3)

Tritherapy

49 (28.3)

Quadritherapy

22 (12.7)

 

Profile of ADRs, causality, severity and preventability assessment:

The most frequently administered agents were vincristine (16.3%, n=65) followed by etoposide (14%) and cytarabine (13%). Anthracyclines, doxorubicin and daunorubicin, (21.1%) were the most common class of administered drugs. Among associations of drug, the combination of vincristine, ifosfamide, doxorubicin and etoposide -VIDE (21.2%) was the most commonly used, followed by the combination of cytarabine and daunorubicin (15.2%) and cytarabine, daunorubicin and etoposide association (10.6%).

 

A total of 266 ADRs were reported. 147(55.3%) were presented by the male patients. The types of ADRs according to the CTCAE classification by class of organ affected were: Blood and lymphatic system (33.1%), Gastrointestinal (22.6%), Infections and fevers (17.7%), Respiratory (5.7%), Metabolism and nutrition (3.4%), Nervous system (3.4%), Skin (2.6%), General disorders and administration site abnormalities (2.6%), Hepatic (2.3%), Kidney and urinary system (1.9%), Cardiac (1.1%), and Eye disorders (1.1%). The most common adverse events were anemia (14.3%) followed by infections (9.4%), leukopenia (8.7%) and fever (8.3%). Febrile neutropenia accounted for 2.6% of ADRs. The distribution of ADRs according to anticancer drugs utilization is presented in table 2. The results of the causality study, the assessment of severity and preventability are shown in table 3.


 

Table 2: Frequency of ADR according to anticancer drugs used during the study

Anticancer drugs

ADRs

Types

Total administration

Infection and fever

Blood disorders

Infections

Fever

Anemia

Neutropenia

Leucopenia

Thrombopenia

Vincristine

37 (14.9)

0

1

0

0

0

0

Ifosfamide

21 (8.5)

1

0

0

1

1

1

Cyclophosphamide

20 (8.1)

2

1

0

0

1

1

Doxorubicin

19 (7.7)

3

2

6

4

6

4

Methotrexate

19 (7.7)

3

0

4

1

3

1

Cytarabine

18 (7.3)

5

7

3

2

1

0

Etoposide

15 (6)

1

1

3

0

2

0

Dactinomycin

14 (5.6)

0

0

1

0

0

0

Daunorubicin

10 (4)

0

0

1

3

2

0

Cisplatin

8 (3.2)

1

0

1

0

0

1

Carboplatin

3 (1.2)

0

2

0

0

2

1

Bleomycin

2 (0.8)

0

0

0

0

0

0

Cytarabine and Daunorubicin ± Etoposide

34 (13.7)

8

5

13

2

2

2

VIDE#

28 (11.3)

1

3

6

0

3

3

Total

248 (100)

25 (9.4)

22 (8.3)

38 (14.3)

13 (4.9)

23 (8.6)

14 (5.3)

 

Anticancer drugs

ADR

Types

Gastrointestinal disorders

Respiratory failure

Liver Failure

Rash

Fatigue

Others ADRs

Total ADRs per drug

Nausea

Vomiting

Mucositis

Miscellaneous*

Vincristine

1

2

0

4

1

0

0

0

3

12 (4.5)

Ifosfamide

2

2

1

0

0

0

0

0

2

11 (4.1)

Cyclophosphamide

0

0

0

0

2

1

0

0

3

11 (4.1)

Doxorubicin

0

0

3

4

0

0

1

0

3

36 (13.5)

Methotrexate

0

1

1

0

0

1

0

4

7

26 (9.8)

Cytarabine

1

2

5

1

2

1

3

0

14

47 (17.7)

Etoposide

0

1

0

2

0

1

1

0

4

16 (6)

Dactinomycin

0

0

0

1

0

0

0

0

0

2 (0.8)

Daunorubicin

0

1

2

0

1

0

0

0

5

15 (5.6)

Cisplatin

0

0

0

0

0

1

0

0

4

8 (3)

Carboplatin

0

0

0

2

0

0

0

0

1

8 (3)

Bleomycin

0

0

2

3

0

0

0

0

0

5 (1.9)

Cytarabine and Daunorubicin ± Etoposide

3

1

2

2

0

0

0

0

3

43 (16.2)

VIDE#

1

1

2

4

0

0

0

0

2

26 (9.8)

Total

8 (3)

11 (4.1)

18 (6.8)

23 (8.6)

6 (2.3)

5 (1.9)

5 (1.9)

4 (1.5)

51 (19.2)

266 (100)

* Dysphagia, abdominal pain, diarrhea, dental pain, constipation and gingivitis

# VIDE: Vincristine, Ifosfamide, Doxorubicin and Etoposide

 


Table 3: Causality study, assessment of severity and preventability

Variables

n (%)

Causality

 

Possible

105 (39.5)

Probable

148 (55.6)

Certain

13 (4.9)

Severity

Mild

156 (58.6)

Moderate

107 (40.2)

Severe

3 (1.1)

Preventability

Definitely

37 (13.9)

Probably

168 (63.2)

Not

61 (22.9)

 

DISCUSSION:

Incidence of ADRs:

The purpose of this study was to determine the incidence of ADRs induced by anti-cancer drugs in pediatric hematology-oncology hospitalized patients. Results showed that 89.8% of patients hospitalized and receiving chemotherapy had an ADR. This showed the impact that anticancer drug toxicity could have on the pediatric patient. Anticancer drugs are drugs with a narrow therapeutic index and are prone to high toxicity. This incidence was similar to the result of the study by Opanga et al.33 which found an ADR incidence of 93% in pediatric patients with non-Hodgkin's lymphoma. This was also similar to studies by Antony et al (83.33%) and Prasad et al (86.53%) in adults20,34. The incidence found was similar in both males (91%) and females (88%). This was inconsistent with the majority of similar studies in the adult population where females had the most ADRs21,22,35. This is often explained in the literature by sex differences in pharmacokinetics and pharmacodynamics and mainly hormonal changes36. In our case, pediatric patients have different specificities from those of adults.

 

In our study, there was a male predominance. Leukemia was the most common type of cancer (39.7%) followed by neuroblastoma (14.2%) and Ewing sarcoma (12.3%). Indeed, in our context, cancer incidence is twice as high in males as in females37. Leukemia is the most common childhood cancer in Morocco and in the world38,39. Neuroblastoma and Ewing sarcoma are cancers commonly treated in-patient with long-term administration regimens like VIDE and they require close monitoring.

 

Profile of ADRs:

Hematological adverse events were the most common in our study, with a prevalence of 33.1% (n=88), mainly anemia (14.3%). These ADRs were very frequent because anti-cancer agents do not have specific activity against rapidly multiplying cells. Thus, these drugs destroy not only cancer cells but also normal cells, mainly of bone marrow and gastrointestinal tract. This leads to a decrease in blood cells and higher manifestations of gastrointestinal disorders such as nausea and vomiting. Gastrointestinal disorders were the second most frequent ADRs with a prevalence of 22.6% (n = 60). It should be noted that several sociodemographic, clinical and other treatment-related factors might influence the ADRs predominantly found.

 

Chemotherapy-induced nausea and vomiting (CINV) accounted for 7.2% of ADRs. These types of ADRs were less frequent, which can be explained by the good use of antiemetics or the efficacy of ondansetron (5-HT3 antagonist) but also by the low frequency of use of cisplatin, which is a highly emetogenic agent. There is evidence that good prevention can reduce the incidence of CINV20,40.

 

Infection was the most common type of ADR (9.4%) after anemia. Infection is recognized as an ADR of chemotherapy in children41,42. It can be the most common ADRs in oncology21. However, most studies do not describe them as ADRs. These Infections are due to the weakening of the immune system caused by myelosuppressive anti-cancer drugs. In developing countries, mortality associated with infection can be very high7. It is therefore important to reduce delays in antibiotic treatment and hospitalization.

Suspected anti-cancer drugs:

Vincristine was the most commonly administered drug (16.3%) ahead of etoposide and cytarabine. However, cytarabine was the drug mostly involved in ADRs. Vincristine is an antineoplastic vinca-alkaloid with good tolerance in children and is indicated in the treatment of many hematological cancers but also tumors and sarcomas. It is part of the majority of therapeutic protocols, which could explain its high frequency of use in our study. Cytarabine, an antimetabolite indicated for the treatment of leukemia, on the other hand, is highly cytotoxic and is sometimes used at high doses for treating acute myeloid leukemia in children7,43,44. Pediatric patients receiving a regimen based on combination of cytarabine and anthracyclines, especially those with acute myeloid leukemia should receive more attention in terms of prevention and management of ADRs. In a previous study in the same DPHO, patients with acute myeloid leukemia experienced the majority of febrile neutropenia (31.5%)45.

 

Causality study, assessment of severity and preventability:

According to the WHO causality method, 55.6% of ADRs were probable, 39.5% were possible and 4.9% were certain. According to the preventability obtained using the modified Shomock and Thoronton scale, 63.2% of ADRs were probably preventable, 22.9% were not preventable, and 13.9% were definitely preventable. These figures were consistent with similar studies that found a predominance of hematological ADRs35.

 

The majority of ADRs regardless of severity were managed during the study. This is the case of neutropenia treated with filgrastim, which is difficult to access. Pain was treated largely with opioids. In our institution, multidisciplinary means were implemented for an internal management of opioid stocks directly by the DPHO.

 

Our study also provided epidemiological data on the use of anticancer drugs in pediatric oncology settings. For example, regimens combining cytarabine and daunorubicin were the most commonly administered mainly for treating acute lymphoblastic leukemia, followed by the VIDE combination for Ewing sarcoma. Anthracyclines were the most commonly used class of anticancer drugs and the most involved in ADRs. Data from anticancer drug utilization are needed to better understand the profile of ADRs observed.

 

However, there were some limitations to this study, such as the small size of the study population, which may not help to identify differences if they exist between the sexes and ages of patients. In addition, the duration of the study was short, which may mask the actual safety of platinum derivatives (cisplatin and carboplatin) which have a low frequency of use in the study population. Finally, it was a global descriptive approach to ADRs that did not take into account the severity grading scale of the tool used30. This is the first national and regional study conducted in children, intended to provide baseline data for subsequent studies considering a regimen, cancer type or drug approach.

 

CONCLUSION:

Through this study, we determined a high incidence of chemotherapy-induced ADRs in pediatric cancer patients. The most commonly reported adverse events were anemia followed by infections and were mild in severity. These results were similar to previous studies on the subject. Our study provided also an overview of the use of anticancer drugs and their degree of involvement in ADRs. These informations can be useful in clinical practice to categorize and prevent preventable adverse events according to the frequency of use of each type or class of anticancer drugs used in pediatric hematology-oncology. It can have an impact on the rapid detection and management of ADRs at local level and thus on the health status and resources deployed. They are also important data for the choice of anti-cancer drugs and adjuvants used. This study therefore emphasizes on the importance of adverse reaction reporting in hospital, especially in pediatric settings. Awareness-raising among healthcare professionals but also among patients and parents is required.

 

CONFLICT OF INTEREST:

No conflicts of interest.

 

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Received on 25.06.2020           Modified on 16.01.2021

Accepted on 07.05.2021         © RJPT All right reserved

Research J. Pharm. and Tech. 2022; 15(6):2559-2564.

DOI: 10.52711/0974-360X.2022.00428